Patients with anthrax infection recognized at late stages have high mortality even with appropriate antibiotic therapy (MMWR Morb. Mortal Wkly. Rep. 50:1049-51, 2001), which is likely due to the effects of bacterial toxins that persist following death of the pathogen. One of these toxins, anthrax lethal toxin (LT), includes three distinct components: anthrax protective antigen (PA), anthrax edema factor (EF), and anthrax lethal factor (LF). Anthrax PA binds target cells and allows entry of the enzymatically active anthrax LF (Lacy and Collier, Curr. Top. Microbiol. Immunol. 271:61-85, 2002). LF, in turn, inactivates mitogen activated protein kinase kinases (MAPKKs) through cleavage at specific recognition sites (Moayeri et al. J. Clin. Invest. 112:670-82, 2003; Duesbery et al., Science 280:734-7, 1998; Vitale et al., Biochem. Biophys. Res. Commun. 248:706-11, 1998; Pellizzari et al. FEBS Lett. 462:199-204, 1999; and Park et al., Science 297:2048-51, 2002). MAPKKs are intermediates in signal transduction cascades that ultimately lead to activation of the NF-κB family of transcription factors that promote macrophage survival (Park et al., Science 297:2048-51, 2002).
Although some of the elements underlying the mechanism of action of anthrax LT-induced apoptosis have been determined, the etiology of species- and cell-specific differences in sensitivity to anthrax LT remains unclear. In addition, the role of other downstream effectors, such as cytokines, is disputed. In this regard, seemingly contradictory reports have been published that either support or reject roles for pro-inflammatory cytokines in responses to anthrax LT in vitro (Hanna et al. Proc. Natl. Acad. Sci. USA 90:10198-201, 1993; Erwin et al., Infect. Immun. 69:1175-7, 2001). Therefore, a clearer understanding of downstream effectors is needed. Such an understanding will permit identification of agents that can be used to treat or diagnose an anthrax infection, as well as methods of treating or diagnosing an anthrax infection.